Cancer uses antioxidants to disarm the immune system, scientists discover

Scientists have discovered that certain immune cells actually need small amounts of reactive oxygen species, a group of molecules that includes free radicals, to recognize and destroy cancer cells. Even more surprisingly, tumors appear to exploit this requirement by releasing natural antioxidants that interfere with the immune system's ability to fight back.

The findings, published in the journal Science, reveal a previously unknown way that cancer evades the body's defenses. They could also point toward new strategies for making cancer immunotherapies more effective, particularly in patients whose tumors resist existing treatments.

How Cancer Uses Antioxidants to Disable Immune Cells

The immune system protects the body by identifying and eliminating threats, ranging from harmful bacteria and viruses to abnormal cells that can develop into cancer. Among its most important defenses are specialized immune cells called T cells, which can recognize and destroy tumor cells.

However, these cancer-fighting cells depend on chemical signals to activate their destructive abilities. Small amounts of reactive oxygen species provide some of those signals, helping T cells switch into attack mode.

Researchers at the University of Cambridge in the United Kingdom and Oregon Health & Science University in the United States discovered that tumors can interfere with this process. By examining the fluid surrounding cells inside tumors grown in mice, they found that cancer cells create chemical conditions that effectively prevent nearby T cells from activating.

The key is a naturally occurring antioxidant protein called Peroxiredoxin 1 (PRDX1). Cancer cells release large quantities of this protein into their surroundings, where it removes the reactive oxygen species that T cells need to function. Without those activating signals, the immune cells become less effective at destroying cancer.

In effect, tumors use antioxidants as a chemical shield, weakening the immune response that would otherwise threaten their survival.

Removing Cancer's Antioxidant Shield Slows Tumor Growth

To investigate whether this defense mechanism could be disrupted, the researchers used CRISPR gene editing to modify cancer cells in mice. The edited cells could no longer produce PRDX1, allowing the team to examine what happened when tumors lost their ability to release the antioxidant protein.

The results were encouraging. Without PRDX1, immune cells became more active, and tumor growth was reduced. This suggested that interfering with the antioxidant protein could restore some of the immune system's ability to attack cancer.

The researchers then investigated whether human cancers use the same strategy. They examined existing data on proteins released by human cancer cell lines, studied patterns of gene activity in thousands of human tumors, and analyzed fluid collected from tumors surgically removed from patients.

All three lines of evidence supported the same conclusion. Human cancers also release PRDX1 into the surrounding environment, where it can eliminate the reactive oxygen species that cancer-fighting T cells rely on.

Dr. Xan Wesolowski, one of the lead authors from the University of Cambridge's Department of Pathology, explained why the discovery challenges conventional thinking about these molecules.

"We tend to think of reactive oxygen species purely as damaging byproducts of metabolism. But we are increasingly understanding they have important functions within cells, and T cells need them to activate. Our study develops this picture, revealing that tumors can exploit this very dependency to evade elimination."

A New Strategy for Making Cancer Immunotherapy More Effective

Cancer treatment has increasingly focused on helping the immune system recognize and eliminate malignant cells. These approaches, known as immunotherapies, have produced remarkable results for some patients, but many others experience little or no benefit.

The new research identifies a possible reason certain tumors can withstand immune attacks. By releasing PRDX1, cancer cells may suppress the very T cells that immunotherapies are designed to activate.

Importantly, the researchers found that preventing cancer cells from producing this antioxidant improved their response to immunotherapy in experimental models. Some tumors that had previously resisted treatment became responsive when the antioxidant defense was disrupted.

Professor Rahul Roychoudhuri, also from Cambridge's Department of Pathology, said the findings identify a promising target for future cancer treatments.

"We've found a new way by which cancers shut down the immune system. When we block this process, tumors that don't respond to some immunotherapies start responding to treatment. That tells us this is a pathway worth targeting therapeutically, and there are several ways we might be able to achieve this."

The discovery also raises the possibility of using a different type of chemical approach to strengthen the immune response.

Dr. Robert Eil from the School of Medicine at Oregon Health & Science University said: "Our study suggests a possible way to boost T cell immunotherapies. Rather than using antioxidants, it could be that prooxidants can kickstart the T cells into action against tumor cells."

Why the Findings Raise Questions About Antioxidant Supplements

Beyond their potential implications for cancer treatment, the results may help explain a longstanding puzzle involving antioxidant supplements.

Antioxidants have frequently been promoted for their ability to neutralize reactive oxygen species and protect cells from damage. Because these molecules can contribute to processes associated with cancer development, researchers have investigated whether taking antioxidant supplements might reduce cancer risk.

However, several large randomized clinical trials have failed to demonstrate such protection. In some cases, antioxidant supplementation has even been associated with worse outcomes.

The new findings suggest one possible explanation. Although reactive oxygen species can damage cells, they also help activate the immune defenses that fight cancer. Removing too many of these molecules could unintentionally interfere with the immune system's ability to recognize and destroy tumors.

This does not establish that antioxidant supplements generally promote cancer, but it highlights the importance of understanding how these molecules behave in different biological settings.

The researchers also emphasize that their experimental findings remain preclinical. Although they identified evidence of the same antioxidant mechanism in human cancers, the potential treatment strategies have not yet been established as safe or effective in patients.

People living with cancer should therefore not change their diets, supplement use, or medical treatments based on these findings without consulting a healthcare professional.

The research was largely supported by the Medical Research Council, the European Research Council, Wellcome, and the National Institutes of Health/National Cancer Institute.